Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

Cheng, Binbin; Wang, Wei; Niu, Xiaoge; Ren, Yichang; Liu, Ting; Cao, Hao; Wang, Shuanghu; Tu, Yingfeng; Chen, Jingxuan; Liu, Shuwen; Yang, Xu-chao; Chen, Jianjun

doi:10.1021/acs.jmedchem.0c01684

Cited by 34 publications

(38 citation statements)

References 19 publications

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“…In an attempt to overcome some of these problems, a number of small molecules, such as macrocyclic peptides and organic compounds targeting PD-L1, have been reported, initially only in patent applications. − BMS first patented a series of biphenyl ether-based compounds (eg., 1 , also known as BMS-202, see Chart ) able to disrupt the PD-1/PD-L1 complex with an IC 50 ranging between 1 and 300 nM. , Only in 2015, the structural basis for the human PD-1/PD-L1 protein–protein interaction was unraveled by X-ray crystallography . Later on, structures of PD-L1 complexed with antibodies, peptide macrocycles, and small organic compounds (eg., 1 ) have been released too, ,, revealing that ligands can recognize partially overlapping regions on the PD-L1 surface. ,,− However, the flat and hydrophobic binding surface of PD-L1 made it immediately clear that the rational design of small inhibitors would have been all but easy.…”

Section: Introductionmentioning

confidence: 99%

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Interfering with the Tumor–Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors

et al. 2021

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The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number of cancers. However, a novel class of small organic molecules, with BMS-202 (1) as the lead, is emerging as direct PD-L1 inhibitors. Herein, we report a series of 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized and assayed for their PD-L1 binding by NMR and homogeneous time-resolved fluorescence. Among them, compound 10 demonstrated to strongly bind with the PD-L1 protein and challenged it in a co-culture of PD-L1 expressing cancer cells (PC9 and HCC827 cells) and peripheral blood mononuclear cells enhanced antitumor immune activity of the latter. Compound 10 significantly increased interferon γ release and apoptotic induction of cancer cells, with low cytotoxicity in healthy cells when compared to 1, thus paving the way for subsequent preclinical optimization and medical applications.

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Section: Introductionmentioning

confidence: 99%

“…In this scenario, the discovery of 1 has represented a precious starting point for ligand-based design or “me too” strategies that led to the discovery of compounds 2-6 (Chart ). − ,, …”

Section: Introductionmentioning

confidence: 99%

Interfering with the Tumor–Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors

et al. 2021

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“…Despite the difference in binding constants, a classical mouse model was used for the study of in vivo bioactivity of the compound. In another study, resorcinol derivatives of biphenyls were shown to bind to the mouse and human PD-L1 with comparable affinities [15]. Such a characteristic seem to justify the use of non-humanized, classical, immunocompetent mouse models.…”

Section: Specificity Towards the Human And Mouse Pd-l1mentioning

confidence: 94%

“…The numeric data are also presented in Table 1. The molecules represent biphenyls [3][4][5][12][13][14][15][16], terphenyls [17,18], biphenyls with a ring fusion [19], elongated biphenyls [20], symmetric biphenyls [21][22][23], and macrocyclic peptides [10,11,24,25]. 1.…”

Section: The Comparison Of In Vitro Activitiesmentioning

confidence: 99%

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PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

Surmiak

Magiera‐Mularz

Musielak

et al. 2021

IJMS

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Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.

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A combined approach of structure‐based virtual screening and NMR to interrupt the PD‐1/PD‐L1 axis: Biphenyl‐benzimidazole containing compounds as novel PD‐L1 inhibitors

Donati,

Viviano,

D'Amore

et al. 2023

Archiv der Pharmazie

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Immunotherapy has emerged as a game‐changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD‐1/PD‐L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest. In an attempt to find novel chemotypes, a virtual screening approach was employed, resulting in the identification of new chemical entities with a certain binding capability, the most versatile of which was the benzimidazole‐containing compound 10. Through rational design, a small library of its derivatives was synthesized and evaluated. The homogeneous time‐resolved fluorescence (HTRF) assay revealed that compound 17 shows the most potent inhibitory activity (IC50) in the submicromolar range and notably, differently from the major part of PD‐L1 inhibitors, exhibits satisfactory water solubility properties. These findings highlight the potential of benzimidazole‐based compounds as novel promising candidates for PD‐L1 inhibition.

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Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

Cited by 34 publications

References 19 publications

Interfering with the Tumor–Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors

Interfering with the Tumor–Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

A combined approach of structure‐based virtual screening and NMR to interrupt the PD‐1/PD‐L1 axis: Biphenyl‐benzimidazole containing compounds as novel PD‐L1 inhibitors

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